1. Field of the Invention
This invention relates to biomedical devices, and more specifically relates to a method for covalent immobilization of an antithrombogenic agent onto a substrate.
2. Background of the Invention
Extensive investigations have been undertaken over many years to find materials that will be biologically and chemically stable toward body fluids. This area of research has become increasingly important with the development of various objects and articles which must be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters and the like.
Synthetic plastics have come to the fore as preferred materials for such articles. However, these materials have the major drawback of being thrombogenic. Thrombogenicity has conventionally been counteracted by the use of anticoagulants such as heparin. Various procedures for attachment of heparin to otherwise thrombogenic polymeric surfaces have been disclosed. In one method taught by R. I. Leininger and G. A. Grode, U.S. Pat. No. 3,457,098, a quaternary amine is incorporated into an epoxy resin. Subsequent exposure to sodium heparinate dissolved in water then results in ionically bound heparin. The polymer systems are essentially rigid epoxy resins which are not suitable for forming medical devices such as catheters or other devices requiring extrusion. These polymers also are not appropriate where flexibility in the device is required.
Leininger et al., in U.S. Pat. No. 3,617,344 discloses a method in which a polymeric surface is chemically modified to include a chloromethyl group. Amination of the chloromethyl group provides a quarternary ammonium halide. Reaction of the halide with sodium heparin results in ionic bonding of the heparin to the surface.
A related approach for ionic binding has been described by Eriksson et al. in U.S. Pat. No. 3,634,123. An article having a plastic surface is heated to near or above its softening point in an aqueous solution of a cationic surface active agent, such as a long chain alkylamine or alkylenediamine hydrohalide. The solution is preacidified to a pH of 7.0 or lower. Subsequent digestion of the plastic article with an aqueous solution of heparin results in an article having about 0.1 International Unit of heparin thereon.
Williams et al., in U.S. Pat. Nos. 4,349,467 and 4,613,517 disclose modifications of the surface active agent-heparin method. The former patent discloses that higher quantities of heparin are attached to a plastic surface by using more concentrated solutions of heparin. The latter patent discloses treating a polymeric surface with a plasma, digesting the plasma-treated surface with a quaternary ammonium salt, reacting the salt with sodium heparin, and crosslinking the heparin with glutaraldehyde.
Covalent conjugation of heparin to a polymeric article coated with an amine-rich surface is disclosed in U.S. Pat. No. 4,521,564 to Solomon et al. In an improvement disclosed by Hu et al. in U.S. Pat. No. 4,720,512, fluorine atoms are plasma deposited onto the amine-rich surface of Solomon et al. prior to heparinization.
Polyurethanes containing segments derived from both perfluoroalkyl substituted diols and polysiloxane diols are disclosed by Mueller in U.S. Pat. No. 4,098,742.
U.S. Pat. No. 4,810,749 to Pinchuk discloses fluorinated polyurethanes prepared from fluorinated polysiloxane diols.
Copending application Ser. No. 173,892, of common assignee herewith discloses fluorinated polyetherurethanes and medical devices fabricated therefrom.
While significant advances have been made toward antithrombogenic surfaces for fabrication of medical devices, further improvements are needed. In particular, materials having surfaces that are essentially non-thrombogenic for use in devices which will be in contact with blood for prolonged periods are needed. It is toward fulfillment of this need that this invention is directed.